Methamphetamine (MA) is a common drug of abuse in the United States and is associated with increased frequency of high-risk sexual behavior leading to human immunodeficiency virus type 1 (HIV-1) exposure. Infection with HIV-1 can lead to HIV-associated dementia (HAD) and other co-morbidities like fatigue and depression. It has become apparent that HIV-1 infected individuals who abuse MA are more likely to experience neurobehavioral complications than are HIV-1 infected non-users. We propose that this is because MA sensitizes cells in the brain, particularly microglia, to HIV-1 proteins. HIV-1 infects microglial cells but because neurons are not productively infected by HIV-1, the development of neurobehavioral complications is thought to be due to soluble factors released by infected or activated microglia such as inflammatory cytokines. That MA abuse may activate or sensitize microglial cells and promote neuroinflammation in HIV-1 patients is highly relevant to HAD and other AIDS co-morbidities. Thus, if MA sensitizes the brain by increasing the number of activated microglia and/or potentiating the release of inflammatory cytokines and neurotoxic products in response to HIV-1 proteins, this might explain why infected drug users are more likely to develop neurobehavioral complications than infected non-users. Unfortunately, the relationship between MA abuse, neuroinflammation, and HAD and other AIDS co-morbidities has not been explored. Therefore, the goal of this proposal is to investigate if MA use and HIV-1 infection unite to exacerbate the cognitive and motor complications associated with HIV disease and produce a heightened neuroinflammatory state. In the first aim, mice sensitized to MA through daily i.p. injections will be injected i.c.v. with vehicle or HIV-1 gp120 and the cognitive effects of MA and gp120 will be explored by utilizing two different learning paradigms: a) an associative learning task that is considered striatal-dependent; and b) a spatial learning task that is considered hippocampal-dependent. This methodology allows for the delineation of cognitive changes that may occur due to alterations in these discrete brain areas. Furthermore, motor learning and coordination will be assessed on a Rota-rod. Similar studies will be conducted using a Tat transgenic mouse model in which targeted Tat expression is linked to a doxycycline-inducible GFAP promoter. The second aim will determine if MA sensitization exacerbates the production of inflammatory cytokines after exposure to HIV proteins. Inflammatory cytokines will be measured in hippocampal and striatal tissue obtained using laser capture microdissection techniques; and cytokine-positive microglia will be localized by immunohistochemical staining. Special attention is paid to the striatum because MA alters motor activity by inducing dopamine release at this site, and the hippocampus because it is densely populated with microglia and is involved in cognitive disorders that are evident in patients with HAD. In addition to inflammatory cytokines, treatment effects on the dopaminergic and serotoninergic systems will be measured. The proposed studies are critically needed to understand the insidious relationship between drug abuse, HIV-1 infection, and HAD. Methamphetamine abuse is associated with increased frequency of high-risk sexual behavior leading to HIV-1 exposure and it has become apparent that HIV-1 infected individuals who abuse MA are likely to experience more severe cognitive and motor complications than are non-users which may be due to an increase in neuroinflammation. Given the increasing number of HIV-1 infected persons that also abuse MA, a better understanding of how MA influences the neurobehavioral complications associated with HIV-1 infection is needed. Therefore, the goal of this proposal is to investigate if MA use and HIV-1 infection unite to exacerbate the cognitive and motor complications associated with HIV disease and produce a heightened neuroinflammatory state. [unreadable] [unreadable] [unreadable]